Although the majority of the patients with epilepsy have their seizures successfully controlled by currently available medications, approximately one third continue to have seizures in spite therapy attempts with multiple medications. This group of patients is defined as therapy resistant, and it is the group that is in greatest need of more effective therapies. Although there is rapidly expanding evidence that there are multiple changes in the brains of therapy resistant patients that may alter the pharmacological response profile, the therapy discovery process has depended on the use of acutely induced seizures in brains from normal animals. It is very likely that this approach fails to address mechanisms of seizure generation and potential seizure suppression that may be unique to therapy resistant epilepsy. This application is in response to a Request for Applications announcement to improve the therapy discovery process for these patients. The RFA is seeking validation of pharmacoresistance in a post status epilepticus model of limbic epilepsy. In the course of this project we will achieve several goals that will meet the primary purpose of this RFA. Overall we will establish a tool that can be used to test potential new therapies, but as steps in meeting this goal we will determine the most efficient way of using the model, and we will create and validate methods for administering therapeutic doses of compounds in a chronic rodent model of epilepsy with intermittent spontaneous seizures. This project will meet the program goals by establishing baseline data and introducing new methods for evaluating the therapeutic potential of novel compounds for the treatment of epilepsy.